Methods and systems for disease treatment using electrical stimulation

ABSTRACT

Systems for disease treatment using electrical stimulation are disclosed. A representative method for treating a patient includes changing an activity, expression, or both activity and expression of a fast sodium channel, a glial cell, or both a fast sodium channel and a glial cell of the patient by applying to a target neural population of the patient an electrical therapy signal having a frequency in a frequency range of 1.5 kHz to 100 kHz.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a continuation of U.S. patent applicationSer. No. 14/300,193, filed Jun. 9, 2014, which claims priority to U.S.Provisional Application 61/833,392, filed on Jun. 10, 2013, which areincorporated herein by reference.

TECHNICAL FIELD

The present disclosure is directed generally to methods and systems fordisease treatment using electrical stimulation. Particular embodimentsinclude changing an activity, expression, or both activity andexpression of a fast sodium channel, a glial cell, or both a fast sodiumchannel and a glial cell of the patient by applying electricalstimulation to a target neural population of a patient.

BACKGROUND

Neurological stimulators have been developed to treat pain, movementdisorders, functional disorders, spasticity, cancer, cardiac disorders,and various other medical conditions. Implantable neurologicalstimulation systems generally have an implantable signal generator andone or more leads that deliver electrical pulses to neurological tissueor muscle tissue. For example, several neurological stimulation systemsfor spinal cord stimulation (SCS) have cylindrical leads that include alead body with a circular cross-sectional shape and one or moreconductive rings (i.e., contacts) spaced apart from each other at thedistal end of the lead body. The conductive rings operate as individualelectrodes and, in many cases, the SCS leads are implantedpercutaneously through a needle inserted into the epidural space, withor without the assistance of a stylet.

Once implanted, the signal generator applies electrical pulses to theelectrodes, which in turn modify the function of the patient's nervoussystem, such as by altering the patient's responsiveness to sensorystimuli and/or altering the patient's motor-circuit output. In SCStherapy for the treatment of pain, the signal generator applieselectrical pulses to the spinal cord via the electrodes. In conventionalSCS therapy, electrical pulses are used to generate sensations (known asparesthesia) that mask or otherwise alter the patient's sensation ofpain. For example, in many cases, patients report paresthesia as atingling sensation that is perceived as less uncomfortable than theunderlying pain sensation.

Aspects of the present disclosure are directed to systems and methodsthat make use of, employ, rely on and/or otherwise use or incorporateaspects the interaction between electrical therapy and the patients towhom the therapy is applied.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a partially schematic illustration of an implantable spinalcord modulation system positioned at the spine to deliver therapeuticsignals in accordance with several embodiments of the presenttechnology.

DETAILED DESCRIPTION

Neurological stimulators have been developed to treat pain, movementdisorders, functional disorders, spasticity, cancer, cardiac disorders,and various other medical conditions. Implantable neurologicalstimulation systems generally have an implantable pulse generator andone or more leads that deliver electrical pulses to neurological tissueor muscle tissue. For example, several neurological stimulation systemsfor spinal cord stimulation (SCS) have cylindrical leads that include alead body with a circular cross-sectional shape and one or moreconductive rings spaced apart from each other at the distal end of thelead body. The conductive rings operate as individual electrodes and, inmany cases, the SCS leads are implanted percutaneously through a largeneedle inserted into the epidural space, with or without the assistanceof a stylet.

Once implanted, the pulse generator applies electrical pulses to theelectrodes, which in turn modify the function of the patient's nervoussystem, such as by altering the patient's responsiveness to sensorystimuli, altering the patient's motor-circuit output, and/or otherwisemodifying other neural function. Example neuromodulation systems,methods, and therapy parameters are described in co-owned publishedpatent applications: US Patent Publication No. 2009/0204173; US PatentPublication No. 2007/0213771; US Patent Publication No. 2010/0191307; USPatent Publication No. 2010/0274312; US Patent Publication No.2010/0274314; US Patent Publication No. 2012/0172946; and US PatentPublication No. 2013/0066411, which are all incorporated herein byreference in their entireties. To the extent the foregoing materialsand/or any other materials incorporated herein by reference conflictwith the present disclosure, the present disclosure controls.

Provided herein are various embodiments of neuromodulation systems,methods, and therapies for the treatment of medical conditions. Thespecific embodiments discussed are not to be construed as limitations onthe scope of the disclosed technology. It will be apparent to oneskilled in the art that various equivalents, changes, and modificationsmay be made without departing from the scope of the disclosedtechnology, and it is understood that such equivalent embodiments are tobe included herein.

The following abbreviations are used herein: AIC, anterior limb internalcapsule; BST, bed nucleus of the stria terminals; CMPF, centromedian andparafascicularis; CNS, central nervous system; DREZ, dorsal root entryzone; GF, genitofemoral; GNI, glial neuronal cell interaction; GPI,globus pallidus internus; MCS, motor cortex stimulation; MD, movementdisorder; MI, primary motor cortex; ONS, occipital nerve stimulation;NAcc, nucleus accumbens; NTS, nucleus tractus solitarii; PVG,periventricular grey matter; PAG, periaqueductal grey matter; PPN,pedunculopontine nucleus; SCA, superior cerebellar artery; SCS, spinalcord stimulation; SMA, supplementary motor area; SPG, sphenopalatineganglion; STN, subthalamic nucleus; Vcpc, ventro caudalisparvocellularis; VIP, ventral intermedia nucleus; VOA, ventralis oralisanterior; VOP, ventralis oralis posterior; VPL, ventral posterolateralnucleus; VPM, ventral posteromedial nucleus; WDR, wide dynamic range;ZI, zona incerta.

Recent animal studies have shown that application of electricalstimulation to the dorsal root entry zone (DREZ) at frequencies between2 kHz and 100 kHz suppresses wide dynamic range (WDR) neuron response by70% in response to noxious stimulation (Cuellar 2012). Inhibition of WDRfiring was found to persist for seconds to minutes after stimulationended. WDR neurons (also known as convergent neurons) are one of threetypes of second order projection neurons. WDR neuron firing iscorrelated with pain perception, with firing rate increasing steadily asstimulus intensity increases. Thus, these data suggest that electricalstimulation at the tested frequencies functions in part by direct axonalinhibition.

Glial cells were traditionally thought to play primarily a structuralrole in the nervous system, for example by surrounding neurons, holdingneurons in place, providing electrical insulation, and destroyingpathogens. However, glial cells may play a role in the transmission ofchronic pain by releasing various mediators such as nitric oxide,proinflammatory cytokines, excitatory amino acids, and prostaglandins.Release of these mediators may cause the release of substance P andexcitatory amino acids by peripheral nerves as well as modify localneural interactions in the CNS, which in turn results in actionpotential generation or neural responses to synaptic inputs. Substance Pand excitatory amino acid release can also further activate glial cells,creating a positive feedback loop. Glial cells form a network withthemselves and communicate via slow inward calcium currents, which areactivated by a variety of factors including potassium. Electricalstimulation with appropriate signal parameters may be used to reduceextracellular potassium levels by primary afferent inhibition, therebyreducing glial cell activity.

Neurons and certain glial cells contain sodium channels that areresponsible for the rising phase of action potentials. When exposed tolow frequencies, all of these sodium channels exhibit changes in theirconductance. At higher frequencies, however, these changes are specificto fast sodium channels such as NaV1.8 and NaV1.9, which are overlyactive in chronic pain. Without being bound to a particular theory,electrical stimulation with appropriate signal parameters may derivepain reduction in part from its ability to change the conductance offast sodium channels in neurons and/or glial cells, thereby specificallydownregulating those sodium channels that are most involved with chronicpain.

As disclosed herein, electrical stimulation, with the therapy signalparameters disclosed herein, can be used to normalize pathologicalneural networks associated with fast sodium channel activity and/orexpression by attenuating pathology-induced sodium channel activity andmodulating glial neuronal cell interaction (GNI). GNI accordingly refersgenerally to interactions with a glial/neuronal component, includinginteractions between (a) glial cells and other glial cells, (b) glialcells and neurons, (c) glial networks and neurons, and/or (d) glialnetworks and neural networks. Based on this, the present applicationprovides methods and devices for attenuating pathology-induced sodiumchannel activity, (and/or other pathology-induced ionophores or membranechannel activity) modulating GNI, and treating various conditionsassociated with fast sodium channel activity and/or expression and GNI.

In certain embodiments, methods are provided for attenuatingpathology-induced sodium channel activity by applying electricalstimulation, with the therapy signal parameters disclosed herein, to atarget tissue or organ. This attenuation may result in decreasedactivity and/or expression of one or more fast sodium channels,including for example NaV1.8 or NaV1.9. In certain embodiments,decreased activity and/or expression of one or more fast sodium channelsresults in decreased glial cell and/or neuronal activity. In certainembodiments, attenuation of pathology-induced sodium channel activitymay also result in increased activity and/or expression of one or moreslow sodium channels, including for example NaV1.3.

In certain embodiments, methods are provided for modulating GNI byapplying electrical stimulation, with the therapy signal parametersdisclosed herein, to a target tissue or organ. In certain embodiments,this modulation may result in a decrease in the release of one or moremediators by glial cells, including for example nitric oxide,proinflammatory cytokines, excitatory amino acids, and prostaglandins.In certain embodiments, this decrease may result in a decrease in actionpotential generation by one or more peripheral nerves or neural elementsin CNS networks, and in certain of these embodiments, the decrease mayresult in reduction or cessation of one or more symptoms of a medicalcondition (e.g., chronic pain).

In certain embodiments, methods are provided for treating a conditionassociated with fast sodium channel activity and/or expression, or acondition for which attenuated fast sodium channel activity and/orexpression is expected to be beneficial, by applying electricalstimulation, with the therapy signal parameters disclosed herein, to atarget tissue or organ. In certain embodiments, the condition beingtreated is selected from the group consisting of a chronic paincondition, a movement disorder, dysautonomia, an anxiety disorder, acognitive disorder, a development disorder, a metabolic disease, or amood disorder.

In certain embodiments, methods are provided for treating a chronic paincondition by applying electrical stimulation, with the therapy signalparameters disclosed herein, to a target tissue or organ. In certain ofthese embodiments the chronic pain condition is a headache painsyndrome, fascial pain syndrome, neck and brachial plexus pain syndrome,shoulder pain syndrome, elbow pain syndrome, other upper extremity painsyndrome, wrist pain syndrome, hand pain syndrome, chest wall painsyndrome, thoracic spine pain syndrome, abdominal & groin pain syndrome,lumbar spine & sacroiliac joint pain syndrome, pelvic pain syndrome, hip& lower extremity pain syndrome, knee pain syndrome, ankle painsyndrome, foot pain syndrome, visceral pain or whole body painsyndromes. In certain of these embodiments, the chronic pain disordermay be a condition listed in Table 1. Table 1 provides various spinalcord, cortical, sub-cortical, and/or peripheral targets for applyingelectrical stimulation in the treatment of each condition. Treatment maybe carried out by applying electrical stimulation to any of the targetslisted, or to a combination thereof. The list of targets is notexhaustive, meaning that there may be one or more additional targets foreach condition.

TABLE 1 Chronic pain conditions Spinal Cord Cortical Sub-CorticalPeripheral Indication Target Target Target Target Headache Pain C2-C4,(e.g., Motor cortex Periventricular Sphenopalatine Syndromes C2-C3)stimulation grey matter ganglion (SPG) (MCS), (PVG), Posteriorperiaqueductal cingulum and grey matter cingulate (PAG), gyrus.(nociceptive pain); internal capsule, ventral posterolateral nucleus(VPL), ventral posteromedial nucleus (VPM) (neuropathic pain) HerpesZoster Appropriate Posterior Ventro caudalis Gasserian (shingles) -spinal level cingulum and parvocellularis ganglion, Trigeminal cingulate(Vcpc), Sphenopalatine gyrus. thalamus, NAcc ganglion (SPG) MigraineC1-C2 Posterior Hypothalamus Sphenopalatine cingulum and ganglion (SPG),cingulate Gasserian gyrus. ganglion, occipital nerve stimulation (ONS)Cluster Hypothalamus SPG, Gasserian ganglion Analgesic Rebound PVG, PAGOccipital Neuralgia C1-C2 PVG, PAG, ONS Vcpc Fascial Pain C2-C4, (e.g.,MCS, Posterior Vcpc, thalamus SPG, Gasserian Syndromes C2-C3) cingulumand ganglion cingulate gyrus. Trigeminal Vcpc, thalamus SPG, GasserianNeuralgia ganglion Temporomandibular Vcpc, thalamus SPG, Gasserian JointDysfunction ganglion, superficial temporal nerve Trigeminal MCS,Posterior Vcpc, thalamus, SPG, Gasserian Neuropathy (aka cingulum andNAcc ganglion, Atypical Facial cingulate gyrus superficial Pain)temporal nerve Myofascial Pain Posterior NAcc SPG, Gasserian Syndrome -Face cingulum and ganglion, cingulate gyrus superficial temporal nerveCancer Pain Insular cortex, PVG, PAG, SPG, Gasserian Posterior nucleusganglion, cingulum and accumbens superficial cingulate gyrus (NAcc),Vcpc temporal nerve Thalamus Hyoid Syndrome C1-C3 SPG, Gasserianganglion, superficial temporal nerve Reflex Sympathetic Insular Cortex,Vcpc, thalamus, SPG, Gasserian Dystrophy-Face Posterior hypothalamusganglion cingulum and cingulate gyrus Neck & Brachial C2-C6, (e.g.,Plexus Pain C3-C4) Syndromes Cervical Facet Appropriate Syndromesomatotopic spinal level Cervical Appropriate Radiculopathy somatotopicspinal level Fibromyalgia - Appropriate Cervical somatotopic Musculaturespinal level Myofascial Pain Appropriate Syndrome - somatotopic Cervicalspinal level Musculature Brachial Plexopathy C3-C8 MCS, Posterior Vcpc,thalamus, (depending on cingulum and PAG, PVG, site of pain) cingulategyrus centromedian and parafascicularis (CMPF), NAcc Pancoast C3-C5Posterior PVG, PAG, Syndrome cingulum and pulvinar cingulate gyrusThoracic Outlet C4 or C8 Syndrome Shoulder Pain C2-C6, (e.g., MCS, ,Vcpc thalamus, Brachial plexus Syndromes C3-C5) Posterior PAG, PVG,cingulum and CMPF, NAcc cingulate gyrus Arthritis Pain - C3-C5 MCS,Posterior Vcpc thalamus, Brachial plexus Shoulder cingulum and PAG, PVG,cingulate gyrus CMPF, NAcc Acromioclavicular C4 Brachial plexus JointPain Myofascial Pain C4 Brachial plexus Syndrome - Shoulders SubdeltoidBursitis C4 Brachial plexus Bicipital Tendonitis C4 Brachial plexusSupraspinatus C2-C4 Brachial plexus Syndrome Rotator Cuff Tear C3-C5(e.g., Brachial plexus post-surgery) Deltoid Syndrome C-C5 Brachialplexus Teres Major C3-C6 Brachial plexus Syndrome Scapulocostal C3-C7Brachial plexus Syndrome Elbow Pain C2-C6, (e.g., Brachial plexus/Syndromes C3-C5) ulnar nerve Arthritis Pain-Elbow C4-C8 Tennis ElbowC6-C8 Golfer's Elbow C6-C8 Anconeus C6-C8 Compartment Syndrome SupinatorC6-C8 Syndrome Brachioradialis C6-C8 Syndrome Ulnar Nerve C6-C8Entrapment At The Elbow Lateral Antebrachial C6-C8 Cutaneous NerveSyndrome Olecranon Bursitis C6-C8 Other Upper C2-C6, (e.g., Brachialplexus Extremity Pain C3-C5) Syndromes Phantom Limb Pain C2-C8, L1-S1MCS, post- Vcpc, cingulum, cingulum, NAcc insula Wrist Pain C2-C6,(e.g., Syndromes C3-C5) Arthritis Pain - Wrist C6-C8 Carpal Tunnel C6-C8(e.g., Syndrome post-surgery) De Quervain's C5-C6 TenosynovitisArthritis Pain - C6-T1 Carpometacarpal Joints Hand Pain C2-C6, (e.g.,Syndromes C3-C5) Arthritis Pain - C5-T1 Fingers Trigger Thumb C5-C7Trigger Finger C5-C7 Ganglion Cysts of C5-C7 Wrist & Hand Sesamoiditisof the C5-C7 Hand Chest Wall Pain T1-T12 Syndromes Intercostal Level ofCostal Nerve Neuralgia neuralgia Post-Thoracotomy Level of Pain surgery+/−1 level Thoracic Spine T1-T12 Pain Syndromes Cancer Pain Level ofpain Insular cortex, PVG, PAG, +2 levels post cingulate cingulum, NAcccortex Costovertebral Center on Arthritis Pain dermatome PostherpeticCenter on NAcc, Vc Center on Neuralgia dermatome Thalmus dermatomeAbdominal & T6-T12 Left vagus nerve, Groin Pain subdiaphragmaticSyndromes right vagus nerve Cancer Pain Insular cortex, PVG, PAG,posterior NAcc, cingulum cingulate cortex Chronic Pancreatitis Insularcortex, Left vagus nerve, posterior subdiaphragmatic cingulate rightvagus nerve cortex Ilioinguinal Ilioinguinal nerve Neuralgia (field app)Visceral Pain Insular cortex, PVG, PAG, Left vagus (peritoneum,posterior NAcc, cingulum stomach, cingulate duodenum, cortex intestine,colon, liver, spleen, pancreas, kidney, adrenal gland, appendix, gallbladder) Post-vasectomy Genitofemoral Pain Syndrome (GF) nerveGenitofemoral GF nerve Neuralgia Lumbar Spine & T8-T12 Insular cortex,PVG, PAG, Sacroiliac Joint post cingulate NAcc, cingulum, Pain Syndromescortex Vcpc Myofascial Pain T8-T12 Syndrome Lumbar Segment Radiculopathyappropriate +/− 2 levels Latissimus Dorsi Upper thoracic Muscle SyndromeArachnoiditis S1-L3 (tune to Insular cortex, PVG, PAG area of pain)posterior NAcc, cingulum cingulate cortex Sacroiliac Joint S1 and L1Insular cortex, Pain post cingulate cortex Pelvic Pain T12-L5 SyndromesCancer Pain NO Insular cortex, PVG, PAG, post cingulate NAcc, cingulumcortex Gluteus Maximus Syndrome Visceral Pain Insular cortex, PVG, PAG,Pudendal nerve (pelvis, coccyx, posterior NAcc, PO ovaries, fallopiancingulate thalamus, tube, uterus, vulva, cortex cingulum clitoris,perineum, urinary bladder, testicles, rectum) Piriformis Insular cortex,Syndrome post cingulate cortex Ischiogluteal Pudendal nerve BursitisLevator Ani S3-S4 Pudendal nerve Syndrome Coccydynia S3-S4 Pudendalnerve Hip & Lower T8-T12 Extremity Pain Syndromes Arthritis Pain - HipT11-L3 Meralgia L1 Paresthetica Phantom Limb Pain MCS Vcpc Knee PainT8-T12 Syndromes Ankle Pain T8-T12 Syndromes Foot Pain T8-T12 SyndromesArthritis - Toe Pain T10-S1 Bunion Pain T10-S1 Plantar Fasciitis T11-L3Calcaneal Spur T11-L3 Syndrome Whole Body Pain C2-C4 Syndromes CancerPain Insula cortex, PVG, PAG, post cingulate cingulum, cortex posteriorthalamus Chronic Regional C4-C8, T8-T12 Insular cortex, Hypothalamus,Pain Syndrome - post cingulate posterior Multiple Limb cortex thalamusPhantom pain Insular cortex, Cingulum, PVG, syndromes posterior PAG,Vcpc, cingulate thalamus cortex, S1, S2 cortex

In certain embodiments, methods are provided for treating a movementdisorder by applying electrical stimulation, with the therapy signalparameters disclosed herein, to a target tissue or organ. In certain ofthese embodiments, the movement disorder may be a condition listed inTable 2. Table 2 provides various spinal cord, cortical, sub-cortical,and/or peripheral targets for applying electrical stimulation in thetreatment of each condition. Treatment may be carried out by applyingelectrical stimulation to any of the targets listed, or to a combinationthereof. The list of targets is not exhaustive, meaning that there maybe one or more additional targets for each condition.

TABLE 2 Movement disorders Spinal Periph- Cord Cortical Sub-Corticaleral Indication Target Target Target Target Akathisia Primary motor STN,Globus (inability cortex (MI), pallidus internus to sit still)supplementary (GPI), ventralis motor area oralis anterior (SMA) (VOA),ventralis oralis posterior (VOP), subthalamic nucleus (STN) AkinesiaSTN, (lack of Pedunculopontine movement) nucleus (PPN), mid-thalamicintralaminar and reticular nuclei Associated MI, SMA GPI, VOA, VOP,Movements STN, zona incerta (Mirror (ZI), area Q Movements orHomolateral Synkinesis) Athetosis MI, SMA GPI, VOA, VOP, (contorted STNtorsion or twisting) Ataxia (gross MI, SMA GPI, VOA, VOP, lack of STNcoordination of muscle movements) Ballismus (violent MI, SMA GPI, VOA,VOP, involuntary rapid STN and irregular movements) Hemiballismus GPi,VoA, VoP, (affecting only STN one side of the body) Bradykinesia MI, SMAGPI, VOA, VOP, (slow STN movement) Cerebral Palsy MI, SMA Deepcerebellar nuclei Chorea (rapid, MI, SMA GPI, VOA, VOP, involuntary STNmovement) Sydenham's MI, SMA GPI, VOA, VOP, Chorea STN Rheumatic MI, SMAGPI, VOA, VOP, Chorea STN Huntington's MI, SMA GPI, VOA, VOP, DiseaseSTN Dystonia MI, SMA GPI, VOA, VOP, (sustained STN torsion) DystoniaDTY1, MI, SMA GPI, VOA, VOP, DTY11 and STN generalized dystoniaBlepharospasm MI, SMA GPI, VOA, VOP STN Writer's Cramp MI, SMA GPI, VOA,VOP STN Spasmodic MI, SMA GPI, VOA, VOP Torticollis STN (twisting ofhead and neck) Dopamine- MI, SMA GPI, VOA, VOP Responsive STN Dystonia(hereditary progressive dystonia with diurnal fluctuation or Segawa'sdisease) Geniospasm MI, SMA GPI, VOA, VOP (episodic STN involuntary upand down movements of the chin and lower lip) Myoclonus MI, SMA GPI,VOA, VOP (brief, STN involuntary twitching of a muscle or a group ofmuscles) Metabolic MI, SMA GPI, VOA, VOP General STN Unwellness MovementSyndrome (MGUMS) Parkinson's Motor cortex, Subthalamic Disease pre-motornucleus, GPI, ZI, cortex pallidofugal fibers Spasms Superior(contractions) cerebellar artery (SCA), Superior Cerebellar structures,deep cerebellar nuc Tardive STN, GPI, VOA, dyskinesia VOP Tic DisordersAnterior limb (involuntary, internal capsule compulsive, (AIC), VOA,repetitive, CMPF thalamus stereotyped) Tourette's AIC, GPI, VOA,Syndrome VOP, STN, CMPF Tremor Ventral (oscillations) intermedia nucleus(VIM), Area Q, ZI Rest Tremor STN, GPI, Area (4-8 Hz) Q, ZI PosturalTremor STN, VIM, Area Q, ZI Kinetic Tremor VIM, Area Q, ZI EssentialTremor VIM, Area Q, ZI (6-8 Hz variable amplitude) Cerebellar tremorVIM, deep (6-8 Hz variable cerebellar nuclei, amplitude) Area QParkinsonian STN +/− VIM tremors (4-8 Hz variable amplitude)Physiological VIM, Area Q, ZI tremor (10-12 Hz low amplitude) Wilson'sdisease VIM and/or STN

In certain embodiments, methods are provided for treating a dysautonomiccondition by applying electrical stimulation, with the therapy signalparameters disclosed herein, to a target tissue or organ. In certain ofthese embodiments, the dysautonomic condition may be a condition listedin Table 3. Table 3 provides various spinal cord, cortical,sub-cortical, and/or peripheral targets for applying electricalstimulation in the treatment of each condition. Treatment may be carriedout by applying electrical stimulation to any of the targets listed, orto a combination thereof. The list of targets is not exhaustive, meaningthat there may be one or more additional targets for each condition.

TABLE 3 Dysautonomic conditions Spinal Cord Cortical Sub-CorticalPeripheral Indication Target Target Target Target Postural OrthostaticT2-T5 insula Hypothalamus Tachycardia Syndrome (POTS) InappropriateSinus T2-T5 insula Hypothalamus Tachycardia (IST) Vasovagal SyncopeT2-T5 insula NTS Neurocardiogenic insula Nucleus tractus Right vagusSyncope (NCS) solitarii (NTS) nerve, left vagus nerve Neurally Mediatedinsula Hypothalamus Hypotension (NMH) Autonomic Instability T2-T5 insula

In certain embodiments, methods are provided for treating an anxietydisorder by applying electrical stimulation, with the therapy signalparameters disclosed herein, to a target tissue or organ. In certain ofthese embodiments, the anxiety disorder may be a condition listed inTable 4. Table 4 provides various spinal cord, cortical, intra-cortical,and/or peripheral targets for applying electrical stimulation in thetreatment of each condition. Treatment may be carried out by applyingelectrical stimulation to any of the targets listed, or to a combinationthereof. The list of targets is not exhaustive, meaning that there maybe one or more additional targets for each condition.

TABLE 4 Anxiety disorders Spinal Cord Cortical Intra-Cortical PeripheralIndication Target Target Target Target Generalized Parietal, Amygdala,Anxiety prefrontal insula, cingulate, Disorder DM thalamus PhobicInsular cortex, Corpus Disorder medial callosum, prefrontal hippocampus,cortex, anterior ventral striatum, cingulate bed nucleus of cortex, thestria ventromedial terminals (BST), prefrontal amygdala, septal cortexnuclei Specific Insular cortex, Amygdala, Phobias (e.g., medial NAcc,septal arachnophobia, prefrontal nuclei acrophobia cortex, anteriorcingulate cortex, ventromedial prefrontal cortex Social Phobias, Insularcortex, Amygdala, (e.g., public medial NAcc, septal speaking, prefrontalnuclei crowded cortex, anterior areas) cingulate cortex, ventromedialprefrontal cortex Agoraphobia Insular cortex, NAcc, BST, medial amygdalaprefrontal cortex, anterior cingulate cortex, ventromedial prefrontalcortex Panic Disorder Insular cortex, NAcc, BST, medial ventralstriatum, prefrontal DM thalamus cortex, anterior cingulate cortex,ventromedial prefrontal cortex Obsessive Cg 25- AIC, CMPF Compulsivecingulate thalamus Disorder cortex, (OCD) orbitofrontal cortex

In certain embodiments, methods are provided for treating a cognitivedisorder by applying electrical stimulation, with the therapy signalparameters disclosed herein, to a target tissue or organ. In certain ofthese embodiments, the cognitive disorder may be a condition listed inTable 5. Table 5 provides various spinal cord, cortical, sub-cortical,and/or peripheral targets for applying electrical stimulation in thetreatment of each condition. Treatment may be carried out by applyingelectrical stimulation to any of the targets listed, or to a combinationthereof. The list of targets is not exhaustive, meaning that there maybe one or more additional targets for each condition.

TABLE 5 Cognitive disorders Spinal Cord Cortical Sub-Cortical PeripheralIndication Target Target Target Target Dementia EntorhinalPrecommissural cortex, fornix hippocampus Amnesia EntorhinalPrecommissural cortex, fornix hippocampus

In certain embodiments, methods are provided for treating a developmentdisorder by applying electrical stimulation, with the therapy signalparameters disclosed herein, to a target tissue or organ. In certain ofthese embodiments, the development disorder may be a condition listed inTable 6. Table 6 provides various spinal cord, cortical, sub-cortical,and/or peripheral targets for applying electrical stimulation in thetreatment of each condition. Treatment may be carried out by applyingelectrical stimulation to any of the targets listed, or to a combinationthereof. The list of targets is not exhaustive, meaning that there maybe one or more additional targets for each condition.

TABLE 6 Development disorders Spinal Cord Cortical Intra-corticalPeripheral Indication Target Target Target Target Motor disorders GPI,VOA, VOP, deep cerebellar nuclei, Cerebellar vermis

In certain embodiments, methods are provided for treating a metabolicdisease by applying electrical stimulation, with the therapy signalparameters disclosed herein, to a target tissue or organ. In certain ofthese embodiments, the metabolic disease may be selected from the groupconsisting of diabetes mellitus, an acid-base imbalance, a metabolicbrain disease, a calcium metabolism disorder, a DNA repair deficiencydisorder, an inborn metabolic error disorder, a mitochondrial disease,or a porphyria, and in certain of these embodiments the metabolicdisease may be a condition listed in Table 7. Table 7 provides variousspinal cord, cortical, sub-cortical, and/or peripheral targets forapplying electrical stimulation in the treatment of each condition.Treatment may be carried out by applying electrical stimulation to anyof the targets listed, or to a combination thereof. The list of targetsis not exhaustive, meaning that there may be one or more additionaltargets for each condition.

TABLE 7 Metabolic diseases Spinal Cord Cortical Sub-Cortical PeripheralIndication Target Target Target Target Diabetes Mellitus Type I DiabetesHypothalamus Splenic and gastric nerve Type II Diabetes HypothalamusSplenic and gastric nerve Acid-Base Hypothalamus, Imbalance subfornicalorgan of pines Acidosis+ Hypothalamus, subfornical organ of pinesAlkalosis+ Hypothalamus, subfornical organ of pines Brain Diseases,Metabolic Hepatic GPI, VOA, VOP, Encephalopathy thalamus (HE)Kernicterus GPI, VOA, VOP, thalamus Mitochondrial GPI, VOA, VOP,Encephalo- thalamus myopathies Wernicke Entorhinal Fornix,Encephalopathy cortex mammillary bodies DNA Repair Deficiency DisordersAtaxia GPI, VOA, VOP, Telangiectasia thalamus Bloom Syndrome GPI, VOA,VOP, thalamus Cockayne GPI, VOA, VOP, Syndrome thalamus Fanconi AnemiaGPI, VOA, VOP, thalamus Metabolism, GPI, VOA, VOP (to Inborn the extentsubjects Errors have movement disorders (MDs) Amino Acid GPI, VOA, VOP(to Metabolism, the extent subjects Inborn Errors+ have MDs) Amino AcidGPI, VOA, VOP (to Transport the extent subjects Disorders, have MDs)Inborn+ GPI, VOA, VOP (to Amyloidosis, the extent subjects Familial+have MDs) Brain Diseases, GPI, VOA, VOP (to Metabolic, the extentsubjects Inborn+ have MDs) Carbohydrate GPI, VOA, VOP (to Metabolism,the extent subjects Inborn Errors+ have MDs) Hyper- GPI, VOA, VOP (tobilirubinemia, the extent subjects Hereditary+ have MDs) Lipid GPI, VOA,VOP (to Metabolism, the extent subjects Inborn Errors+ have MDs)Lysosomal GPI, VOA, VOP (to Storage the extent subjects Diseases+ haveMDs) Metal GPI, VOA, VOP (to Metabolism, the extent subjects InbornErrors+ have MDs) Peroxisomal GPI, VOA, VOP (to Disorders+ the extentsubjects have MDs) Porphyrias+ GPI, VOA, VOP (to the extent subjectshave MDs) Mitochondrial GPI, VOA, VOP (to Diseases the extent subjectshave MDs) Optic Atrophy, CNS Autosomal visual Dominant prosthesis @V1Optic Atrophy, CNS Hereditary, visual Leber prosthesis @V1 Pyruvate GPI,VOA, VOP (to Carboxylase the extent subjects Deficiency have MDs)Disease Pyruvate GPI, VOA, VOP (to Dehydrogenase the extent subjectsComplex have MDs) Deficiency Disease Porphyrias Porphyria, GPI, VOA, VOP(to Erythropoietic the extent subjects have MDs)

In certain embodiments, methods are provided for treating a mooddisorder by applying electrical stimulation, with the therapy signalparameters disclosed herein, to a target tissue or organ. In certain ofthese embodiments, the mood disorder may be a condition listed in Table8. Table 8 provides various spinal cord, cortical, sub-cortical, and/orperipheral targets for applying electrical stimulation in the treatmentof each condition. Treatment may be carried out by applying electricalstimulation to any of the targets listed, or to a combination thereof.The list of targets is not exhaustive, meaning that there may be one ormore additional targets for each condition.

TABLE 8 Mood disorders Spinal Cord Cortical Sub-Cortical PeripheralIndication Target Target Target Target Depressive Dorsolater SubgenualDisorders prefrontal cingulum, cortex, posterior orbitofrontal cingulum,cortex, NAcc, ventral Cg25, capsule/ventral Posterior striatum,cingulate inferior cortex thalamic peduncle, lateral habenula, AIC, BSTMajor Cg25, Subgenual depressive Posterior cingulum, disorder cingulateposterior (MDD) cortex cingulum, NAcc, ventral capsule/ventral striatum,inferior thalamic peduncle, lateral habenula, AIC, BST Dysthymia Cg25,Subgenual posterior cingulum, cingulate posterior cortex cingulum, NAcc,ventral capsule/ventral striatum, inferior thalamic peduncle, lateralhabenula, AIC, BST Double Cg25, Subgenual depression posterior cingulum,cingulate posterior cortex cingulum, NAcc, ventral capsule/ventralstriatum, inferior thalamic peduncle, lateral habenula, AIC, BSTDepressive Cg25, Subgenual Disorder Not posterior cingulum, Otherwisecingulate posterior Specified cortex cingulum, (DD-NOS) NAcc, ventralcapsule/ventral striatum, inferior thalamic peduncle, lateral habenula,AIC, BST

In certain embodiments, methods are provided for treating a visceralpain syndromes by applying electrical stimulation, with the therapysignal parameters disclosed herein, to a target tissue or organ. Incertain of these embodiments, the visceral pain syndrome may be acondition listed in Table 9. Table 9 provides various spinal cord,cortical, sub-cortical, and/or peripheral targets for applyingelectrical stimulation in the treatment of each condition. Treatment maybe carried out by applying electrical stimulation to any of the targetslisted, or to a combination thereof. The list of targets is notexhaustive, meaning that there may be one or more additional targets foreach condition.

TABLE 9 Visceral Pain Syndromes Spinal Cortical Subcortical PeripheralIndication target target target target Cystitis S2-4 Insula, Vcthalamus, Pudendal S1, S2 posterior nerve thalamic nuclei IBS T3-9,Insula, R or L Vagus L1 S1, S2 nerve, splanchnic nerves Mesenteric T3-9,Insula ischemia Idiopathic T3-9 Insula Vc, DM Splanchnic abdominalthalamus, nerve, R or L pain Posterior vagus nerve thalamic nuc.

“Treating” or “treatment” as used herein with regard to a condition mayrefer to preventing the condition, reducing, or ending symptomsassociated with the condition; generating a complete or partialregression of the condition; or some combination thereof. “Preventing”or “prevention” as used herein with regard to a condition may refer tototal or partial prevention of the condition or symptoms associated withthe condition.

In certain embodiments, electrical stimulation is performed with atleast a portion of the therapy signal at a frequency in a frequencyrange between about 2 Hz and about 100 kHz; between about 1.5 kHz andabout 50 kHz; between about 3 kHz and about 20 kHz; between about 3 kHzand about 15 kHz; or between about 5 kHz and about 15 kHz; or atfrequencies of about 5 kHz, about 6 kHz, about 7 kHz, about 8 kHz, about9 kHz, about 10 kHz, about 11 kHz, or about 12 kHz; and in oneembodiment, surprisingly effective results have been found when treatingcertain medical conditions with frequencies between 5 kHz and 15 kHz,and in one embodiment 10 kHz. (The term “about” is intended to represent+/−10%, or a range as would be understood as reasonably equivalent byone of ordinary skill in the art.)

In various embodiments, the electrical stimulation may be applied withat least a portion of the therapy signal at amplitudes within amplituderanges of: about 0.1 mA to about 20 mA; about 0.5 mA to about 10 mA;about 0.5 mA to about 7 mA; about 0.5 mA to about 5 mA; about 0.5 mA toabout 4 mA; about 0.5 mA to about 2.5 mA; and in one embodiment,surprisingly effective results have been found when treating certainmedical conditions with amplitudes below 7 mA.

In various embodiments, the electrical stimulation may be applied withat least a portion of the therapy signal having a pulse width within apulse width range of from about 10 microseconds to about 333microseconds; from about 10 microseconds to about 166 microseconds; fromabout 25 microseconds to about 166 microseconds; from about 25microseconds to about 100 microseconds; from about 30 microseconds toabout 100 microseconds; from about 33 microseconds to about 100microseconds; from about 50 microseconds to about 166 microseconds; andin one embodiment, surprisingly effective results have been found whentreating certain medical conditions with pulse widths from about 25microseconds to about 100 microseconds; and from about 30 microsecondsto about 40 microseconds. In a particular embodiment, the therapy signalat a frequency in a frequency range of 1.5 kHz to 100 kHz, a pulse widthin a pulse width range of 10 microseconds to 333 microseconds and anamplitude in an amplitude range of 0.1 mA to 20 mA. The therapy signalcan be applied at a duty cycle of 5% to 75%, and can be applied tothoracic spinal cord locations to treat back and/or leg pain, e.g.,chronic back and/or leg pain. In another particular embodiment, atherapy signal having a pulse width is applied to the spinal cord at apulse width in a pulse width range of 10 microseconds to 333microseconds at any of a variety of suitable frequencies (within oroutside the range of 1.5 kHz to 100 kHz) to treat a variety of painindications, including but not limited to chronic low back pain and/orleg pain.

Application of electrical stimulation in conjunction with the methodsdisclosed herein can be carried out using suitable devices andprogramming modules specifically programmed to carry out any of themethods described herein. A variety of devices for administering anelectrical signal to a target tissue or organ are taught in thereferences incorporated by reference above. Other examples of devicesfor administering an electrical signal in conjunction with SCS aredisclosed in US Patent Publications Nos. 2010/0274316 and 2010/0211135,both of which are incorporated herein by reference in their entireties.In certain embodiments, a device that is used for applying an electricalsignal to the spinal cord may be repurposed with or withoutmodifications to administer an electrical signal to another targettissue or organ, e.g., a cortical, sub-cortical, intra-cortical, orperipheral target. Electrical stimulation may be applied directly to atarget tissue or organ, or it may be applied in close proximity to thetarget tissue or organ (i.e., close enough for the target tissue ororgan to receive the electrical signal). As such, any of the hereindescribed systems, sub-systems, and/or sub-components serve as means forperforming any of the herein described methods.

In certain embodiments, electrical stimulation is applied to a tissue ororgan using a device that comprises a lead, wherein the lead in turncomprises an electrode. In these embodiments, administration ofelectrical stimulation comprises a positioning step (e.g., placing thelead such that an electrode is in proximity to the target tissue ororgan) and a stimulation step (e.g., transmitting an electrical signal(i.e., therapy signal) through the electrode).

FIG. 1 schematically illustrates a representative treatment system 100for administering electrical stimulation to the spinal cord 191 inconjunction with the methods disclosed herein. The system 100 caninclude a pulse generator 101, which may be implanted subcutaneouslywithin a patient 190 and coupled to a signal delivery element 110. In arepresentative example, the signal delivery element 110 includes one ormore leads or lead bodies 111 (shown as first and second leads 111 a,111 b) that carry features for delivering therapy to the patient 190after implantation. The pulse generator 101 can be connected directly tothe lead 111, or it can be coupled to the lead 111 via a communicationlink 102 (e.g., an extension). Accordingly, the lead 111 can include aterminal section that is releasably connected to an extension at a break114 (shown schematically in FIG. 1). This allows a single type ofterminal section to be used with patients of different body types (e.g.,different heights). The terms “lead” and “lead body” as used hereininclude any of a number of suitable substrates and/or support membersthat carry devices for providing therapy signals to the patient 190. Forexample, the lead 111 can include one or more electrodes or electricalcontacts that direct electrical signals into the patient's tissue. Inother embodiments, the signal delivery element 110 can include devicesother than a lead body (e.g., a paddle) that also direct electricalsignals to the patient 190.

The pulse generator 101 can transmit electrical signals to the signaldelivery element 110 that attenuate pathology-induced sodium channelactivity and/or modulate GNI. The pulse generator 101 can include amachine-readable (e.g., computer-readable) medium containinginstructions for generating and transmitting suitable therapy signals.The pulse generator 101 and/or other elements of the system 100 caninclude one or more processors 107, memories 108 and/or input/outputdevices. Accordingly, the process of providing modulation signals andexecuting other associated functions can be performed bycomputer-executable instructions contained on computer-readable media,e.g., at the processor(s) 107 and/or memory(s) 108. The pulse generator101 can include multiple portions, elements, and/or subsystems (e.g.,for directing signals in accordance with multiple signal deliveryparameters), housed in a single housing, as shown in FIG. 1, or inmultiple housings.

The pulse generator 101 can also receive and respond to an input signalreceived from one or more sources. The input signals can direct orinfluence the manner in which the therapy instructions are selected,executed, updated and/or otherwise performed. The input signal can bereceived from one or more sensors 112 (one is shown schematically inFIG. 1 for purposes of illustration) that are carried by the pulsegenerator 101 and/or distributed outside the pulse generator 101 (e.g.,at other patient locations) while still communicating with the pulsegenerator 101. The sensors 112 can provide inputs that depend on orreflect patient state (e.g., patient position, patient posture and/orpatient activity level, or pathophysiology measurements defined asappropriate to the clinical disorder), and/or inputs that arepatient-independent (e.g., time). In other embodiments, inputs can beprovided by the patient and/or the practitioner, as described in furtherdetail later.

In some embodiments, the pulse generator 101 can obtain power togenerate the electrical signals from an external power source 103. Theexternal power source 103 can transmit power to the implanted pulsegenerator 101 using electromagnetic induction (e.g., radiofrequency (RF)signals). For example, the external power source 103 can include anexternal coil 104 that communicates with a corresponding internal coil(not shown) within the implantable pulse generator 101. The externalpower source 103 can be portable for ease of use. In another embodiment,the pulse generator 101 can obtain the power to generate electricalsignals from an internal power source, in addition to or in lieu of theexternal power source 103. For example, the implanted pulse generator101 can include a non-rechargeable battery or a rechargeable battery toprovide such power. When the internal power source includes arechargeable battery, the external power source 103 can be used torecharge the battery. The external power source 103 can in turn berecharged from a suitable power source (e.g., conventional wall power).

In some cases, an external programmer 105 (e.g., a trial modulator) canbe coupled to the signal delivery element 110 during an initial implantprocedure, prior to implanting the pulse generator 101. For example, apractitioner (e.g., a physician and/or a company representative) can usethe external programmer 105 to vary the modulation parameters providedto the signal delivery element 110 in real time, and select optimal orparticularly efficacious parameters. These parameters can include theposition of the signal delivery element 110, as well as thecharacteristics of the electrical signals provided to the signaldelivery element 110. In a typical process, the practitioner uses acable assembly 120 to temporarily connect the external programmer 105 tothe signal delivery device 110. The cable assembly 120 can accordinglyinclude a first connector 121 that is releasably connected to theexternal programmer 105, and a second connector 122 that is releasablyconnected to the signal delivery element 110. Accordingly, the signaldelivery element 110 can include a connection element that allows it tobe connected to a signal generator either directly (if it is longenough) or indirectly (if it is not). The practitioner can test theefficacy of the signal delivery element 110 in an initial position. Thepractitioner can then disconnect the cable assembly 120, reposition thesignal delivery element 110, and reapply the electrical modulation. Thisprocess can be performed iteratively until the practitioner obtains thedesired position for the signal delivery device 110. Optionally, thepractitioner may move the partially implanted signal delivery element110 without disconnecting the cable assembly 120. Further details ofsuitable cable assembly methods and associated techniques are describedin US Patent Publication No. 2011/0071593, which is incorporated hereinby reference in its entirety.

After the position of the signal delivery element 110 and appropriatesignal delivery parameters are established using the external programmer105, the patient 190 can receive therapy via signals generated by theexternal programmer 105, generally for a limited period of time. In arepresentative application, the patient 190 receives such therapy forone week. During this time, the patient wears the cable assembly 120 andthe external programmer 105 outside the body. Assuming the trial therapyis effective or, shows the promise of being effective, the practitionerthen replaces the external programmer 105 with the implanted pulsegenerator 101, and programs the pulse generator 101 with parametersselected based on the experience gained during the trial period.Optionally, the practitioner can also replace the signal deliveryelement 110. Once the implantable pulse generator 101 has beenpositioned within the patient 190, the signal delivery parametersprovided by the pulse generator 101 can still be updated remotely via awireless physician's programmer (e.g., a physician's remote) 117 and/ora wireless patient programmer 106 (e.g., a patient remote). Generally,the patient 190 has control over fewer parameters than does thepractitioner. For example, the capability of the patient programmer 106may be limited to starting and/or stopping the pulse generator 101,and/or adjusting the signal amplitude.

In any of the foregoing embodiments, the parameters in accordance withwhich the pulse generator 101 provides signals can be modulated duringportions of the therapy regimen. For example, the frequency, amplitude,pulse width and/or signal delivery location can be modulated inaccordance with a preset program, patient and/or physician inputs,and/or in a random or pseudorandom manner. Such parameter variations canbe used to address a number of potential clinical situations, includingchanges in the patient's perception of one or more symptoms associatedwith the condition being treated, changes in the preferred target neuralpopulation, and/or patient accommodation or habituation.

In certain embodiments, electrical stimulation is applied to the dorsalcolumn. In other embodiments, the electrical stimulation is applied toother neural tissue such as nerve roots and peripherals nerves on thespinal level, including for example the dorsal root (DN) and dorsal rootganglion (DRG) and the ventral root (VN). In other embodiments,electrical stimulation may be applied to one or more non-spinal cordtissues or organs. For example, electrical stimulation may be applied tovarious cortical, sub-cortical, intra-cortical, or peripheral targets.For certain conditions, electrical stimulation may be applied to asingle target tissue or organ. For other conditions, electricalstimulation may be applied to multiple target tissues or organssequentially or simultaneously. For example, where the condition is achronic pain disorder, stimulation may be applied to the spinal cord, acortical target, a sub-cortical target, or a combination thereof. Incertain embodiments, electrical stimulation parameters are configured soas to not result in the patient experiencing paresthesia.

In certain embodiments, electrical stimulation is applied at anamplitude that is sub-threshold with regard to paresthesia andsupra-threshold with regard to symptom reduction (e.g., therapy, such aspain relief). In certain of these embodiments, electrical stimulation isapplied at an amplitude between about 0.5 mA to about 20 mA. In certainembodiments, electrical stimulation is applied at a duty cycle. Dutycycles can range from 1% to about 99%, or between about 5% and about75%, or between about 10% and about 50%.

In certain embodiments of the methods provided herein, electricalstimulation may be administered on a pre-determined schedule. In otherembodiments, electrical stimulation may be administered on an as-neededbasis. Administration may continue for a pre-determined amount of time,or it may continue indefinitely until a specific therapeutic benchmarkis reached, for example until an acceptable reduction in one or moresymptoms. In certain embodiments, electrical stimulation may beadministered one or more times per day, one or more times per week, oncea week, once a month, or once every several months. In certainembodiments, administration frequency may change over the course oftreatment. For example, a subject may receive less frequentadministrations over the course of treatment as certain therapeuticbenchmarks are met. The duration of each administration (e.g., theactual time during which a subject is receiving electrical stimulation)may remain constant throughout the course of treatment, or it may varydepending on factors such as patient health, internal pathophysiologicalmeasures, or symptom severity. In certain embodiments, the duration ofeach administration may range from 1 to 4 hours, 4 to 12 hours, 12 to 24hours, 1 day to 4 days, or 4 days or greater.

In certain embodiments of the methods provided herein, administration ofelectrical stimulation may be combined with one or more additionaltreatment modalities. For example, electrical stimulation may be appliedin combination with the administration of one or more pharmaceuticalagents that block fast sodium channels. In other embodiments, electricalstimulation may be used as a replacement for other treatment modalities.For example, electrical stimulation may be administered to a subject whohas previously received neuroleptics or other sodium channel blockersbut who has experienced unsatisfactory results and/or negative sideeffects. In certain embodiments, application of electrical stimulationmay result in a greater treatment effect than administration of othertreatment modalities, including for example a larger reduction insymptoms or an increased duration of symptom reduction.

The following examples are provided to better illustrate the claimedinvention and are not to be interpreted as limiting the scope of theinvention. To the extent that specific materials are mentioned, it ismerely for purposes of illustration and is not intended to limit theinvention. One skilled in the art may develop equivalent means orreactants without the exercise of inventive capacity and withoutdeparting from the scope of the invention. It will be understood thatmany variations can be made in the procedures herein described whilestill remaining within the bounds of the present invention. It is theintention of the inventors that such variations are included within thescope of the invention.

EXAMPLES Example 1

A method of attenuating pathology-induced sodium channel activitycomprising applying electrical stimulation to a target neural location,wherein the electrical stimulation includes one or more systemparameters as described in the embodiments above, and wherein the targetneural location is chosen so as to treat the medical condition listed inTables 1-9 above.

Example 2

A method of treating a condition associated with increased fast sodiumchannel comprising applying electrical stimulation to a target neurallocation, wherein the electrical stimulation includes one or more systemparameters as described in the embodiments above, and wherein the targetneural location is chosen so as to treat the medical condition listed inTables 1-9 above.

Example 3

A method of modulating GNI comprising applying electrical stimulation toa target neural location, wherein the electrical stimulation includesone or more system parameters as described in the embodiments above, andwherein the target neural location is chosen so as to treat the medicalcondition listed in Tables 1-9 above.

Example 4

A neuromodulation system for treating a medical condition comprising: animplantable (or external) pulse generator configured to attenuatepathology-induced sodium channel activity by generating and applying aelectrical stimulation to a target neural location, wherein theelectrical stimulation includes one or more system parameters asdescribed in the embodiments above, and wherein the target neurallocation is chosen so as to treat the medical condition listed in Tables1-9 above.

Example 5

A neuromodulation system for treating a medical condition comprising: animplantable (or external) pulse generator configured to treat acondition associated with increased fast sodium channel by generatingand applying a electrical stimulation to a target neural location,wherein the electrical stimulation includes one or more systemparameters as described in the embodiments above, and wherein the targetneural location is chosen so as to treat the medical condition listed inTables 1-9 above.

Example 6

A neuromodulation system for treating a medical condition comprising: animplantable (or external) pulse generator configured to modulate GNI bygenerating and applying a electrical stimulation to a target neurallocation, wherein the electrical stimulation includes one or more systemparameters as described in the embodiments above, and wherein the targetneural location is chosen so as to treat the medical condition listed inTables 1-9 above.

As stated above, the foregoing is merely intended to illustrate variousembodiments of the present invention. The specific modificationsdiscussed above are not to be construed as limitations on the scope ofthe invention. It will be apparent to one skilled in the art thatvarious equivalents, changes, and modifications may be made withoutdeparting from the scope of the invention, and it is understood thatsuch equivalent embodiments are to be included herein. All referencescited herein are incorporated by reference as if fully set forth herein.

We claim:
 1. A method for treating a patient by changing an expressionof a fast sodium channel of the patient, comprising: using a signalgenerator to generate an electrical therapy signal having a pulse widthin a pulse width range of 10 microseconds to 333 microseconds;transmitting the electrical therapy signal to a signal delivery elementpositioned proximate to a target neural population; applying theelectrical therapy signal to the target neural population, wherein theelectrical therapy signal produces changes in the expression of the fastsodium channel of the patient.
 2. The method of claim 1 wherein theelectrical therapy signal has a frequency in a frequency range of 1.5kHz to 100 kHz.
 3. The method of claim 1 wherein the target neuralpopulation is located in one or more of the patient's tissues.
 4. Themethod of claim 1 wherein the target neural population is located in oneor more of the patient's organs.
 5. The method of claim 1 wherein thetarget neural population is at a peripheral nerve of the patient.
 6. Themethod of claim 1 wherein the target neural population is located in thepatient's central nervous system.
 7. The method of claim 6 wherein thetarget neural population is at the patient's spinal cord.
 8. The methodof claim 7 wherein the target neural population is at a cervicalvertebral level.
 9. The method of claim 7 wherein the target neuralpopulation is at a thoracic vertebral level.
 10. The method of claim 7wherein the target neural population is at a lumbar vertebral level. 11.The method of claim 7 wherein the target neural population is at asacral vertebral level.
 12. The method of claim 7 wherein the targetneural population is at a horsetail region.
 13. The method of claim 1wherein the changes include a downregulation of the expression of thefast sodium channel of the patient.
 14. The method of claim 1 whereinthe changes include a normalization of pathological neural networksassociated with fast sodium channel expression.
 15. The method of claim1 wherein a frequency of the electrical therapy signal affectsexpression of NaV1.8, NaV1.9, or both NaV1.8 and NaV1.9 sodium channelsover another, slower sodium channel.
 16. The method of claim 1, furthercomprising applying the therapy signal to increase expression of theslower sodium channel.
 17. The method of claim 16 wherein the slowersodium channel includes a NaV1.3 channel.
 18. The method of claim 1wherein the changes include an increase in the expression of the fastsodium channel of the patient.
 19. The method of claim 1 wherein thechanges include a decrease in the expression of the fast sodium channelof the patient.
 20. The method of claim 1 wherein the electrical therapysignal has an amplitude in an amplitude range of 0.1 mA to 20 mA. 21.The method of claim 1 wherein the electrical therapy signal has a dutycycle in a duty cycle range of 5% to 75%.
 22. The method of claim 1wherein the electrical signal has a pulse width in a pulse width rangeof 10 microseconds to 333 microseconds and an amplitude in an amplituderange of 0.1 mA to 20 mA.